The intravenous injection of F1 hybrid mice with parental spleen cells resulted in a loss in the ability of the F1 mice to generate T-cell mediated cytotoxic responses in vitro to TNP-self and alloantigens. The loss of response potential depended on the H-2 type of the parental cells, since H-2k,a spleen cells induced unresponsiveness, whereas H-2b spleen cells did not. The phenomenon is: (a) strain-specific (possibly depending on the C57B1/10 genetic background), since strains of mice with other genetic backgrounds injected with parental cells do not exhibit the loss of immune potential; and (b) dependent on a reaction against F1 alloantigens by grafted parental cells (GVH), since loss of immune activity was associated with enlarged F1 host spleens. Suppressor cells were found to be responsible for loss of immune potential. The failure of lymphocytes from parental strains was shown to be due to F1 resistance to parental T cells, which mapped to H-2Db. Protection against GVH-associated suppression could be achieved using anti-H-2 sera directed against specificities of donor or host.